Caloric restriction (CR) increases longevity in mammals. While it is still unclear how CR extends life span, neuroendocrine involvement has been suggested. Leptin is a major hormone involved in energy homeostasis. CR suppresses leptin. Adding leptin to CR animals abolishes effect of CR on the metabolic rate, the immune function and on the gonadotropic, thyrotropic and glucocorticoid axes. Moreover, leptin null mutant ob/ob mice fed ad libitum (AL) and normal CR mice are similar in that both are characterized by suppressed gonadotropic, thyrotropic and somatotropic axes and activated glucocorticoid axis. The major question this proposal addresses is the degree to which the reduction in leptin induced by CR can by itself explain CR effects on the neuroendocrine system, age-related pathologies and life span. By transplanting leptin producing fat from normal lean mice into leptin deficient, ob/ob mice we can create animals whose food intake is matched to that of AL fed normal mice and whose leptin levels are matched to those of CR mice. Thus, we can assess the effects of reduced leptin at the normal food intake. Specific Aim 1 will test whether reducing plasma leptin to CR levels, while maintaining the normal food intake, will mimic CR effects on the neuroendocrine system, specifically on the gonadotropic, thyrotropic, somatotropic and glucocorticoid axes. Specific Aim 2 will test whether reducing plasma leptin to CR levels, at the normal food intake can reduce and postpone age- related pathologies and extend life span. In ob/ob mice, fat transplants will create plasma leptin levels matched to those of CR mice, but will not mimic paracrine and autocrine effects of leptin. To test whether a reduction in leptin PLASMA levels and not other aspects of fat transplantation is sufficient to mimic CR, we will create leptin transgenic mice expressing low levels of leptin and subject them to the same tests as in Specific Aims 1 and 2. Specific Aim 3 will test the hypothesis that the neuroendocrine system, age-related pathologies and life span will be affected similarly in two different models of leptin deficiency, fat transplanted ob/ob mice and leptin transgenics, as long as PLASMA leptin levels are the same.